tbuckley/cabot-search huggingface dataset:
P06.17.A OPTIC NEUROPATHY RELATED TO IMMUNE CHECKPOINT INHIBITORS: A CASE SERIES
Authors: S Cuzzubbo, E Philippakis, B Baroudjian, R Ursu, C Lebbé, A Coutourier, A F Carpentier
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Immune checkpoint inhibitors (ICIs) are associated with a broad spectrum of neurotoxicities. ICI-related optic neuritis have been rarely reported and poorly described. However, their knowledge is essential to promptly recognise and manage them since a persisted visual decline is reported in approximately half of the patients. A systemic steroid treatment has been correlated to a better prognosis. MATERIAL AND METHODS We report a retrospective series of patients with an ICI-related optic neuritis, referred to our departments between 2018 and 2022, with the aim to describe their clinical and para-clinical features and the outcome. Other causes of optical neuropathy were excluded by blood analysis and brain MRI. RESULTS We identified three melanoma patients who developed an ICI-related optic neuropathy. They were treated with combined ipilimumab with nivolumab (n=2) or pembrolizumab monotherapy (n =1). The symptoms occurred after a delay of 43-196 days from ICI initiation and consisted of bilateral painless reduction of visual acuity, associated with colored scotomas in one case and conjunctival erythema in another case. Ophthalmological examination found a bilateral papilledema in all the patients, associated with a panuveitis in one case (patient #1). The presence of papilledema was verified by fundus fluorescein angiography and optic coherence tomography (OCT). Visual evoked potential confirmed a bilateral involvement of optical nerves in two cases, and was normal in the third case, which was thus consistent with a papillitis. ICIs were stopped in patients #1 and #2 and oral steroids started in patient #1. Both patients experienced a complete recovery within 2 weeks from steroids onset and 24 weeks from the last ICI dose, respectively. Given the quick and spontaneous improvement of both symptoms and ophthalmological exam, ICI was continued with the same regimen in patient #3, and the optic neuropathy progressively improved until complete recovery 3 months later. ICI treatment was reintroduced in patient #2 after four months, with no recurrence of the optical neuritis until the last follow up (5 years). CONCLUSION As reported in other series of immune-related optic neuropathies, a bilateral optic nerve involvement with painless decline of vision and papilledema was the most common presentation. Unlike other reports, all the patients of this series experienced a favorable outcome, with total recovery of vision and normalization of the ophthalmological exam. The recovery seems more rapid if patient receive steroids. We reintroduced or continued the ICI in two patients, with no recurrence of optic neuritis, thus suggesting that ICI treatment discontinuation is not mandatory in case of non-severe optical neuropathies. However, a careful analysis of the benefit/risk ratio should be done on a case-by-case basis.
P10.06.B APPLYING TUMOR TREATING FIELDS (TTFIELDS) FOR ENHANCEMENT OF TEMOZOLOMIDE AND LOMUSTINE EFFICACY IN GLIOBLASTOMA CELL LINES
Authors: H Fishman, R Monin, E Dor-On, A Kinzel, A Haber, M Giladi, U Weinberg, Y Palti
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. TTFields therapy concurrent with maintenance temozolomide (TMZ) is approved for treatment of newly-diagnosed glioblastoma (GBM). Recently, benefit was demonstrated in patients with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation for the combination of TMZ with lomustine (CCNU). The addition of adjuvant TTFields to this treatment regimen further improved patient outcomes, leading to a CE mark. The current study aimed to elucidate the mechanism underlying the benefit of this treatment protocol by utilizing GBM cell lines with different MGMT expression status. MATERIAL AND METHODS Human GBM cell lines with different MGMT promoter methylation status [LN-18 (unmethylated MGMT promoter), U-118 MG (partially methylated MGMT promoter), and U-87 MG and LN-229 (methylated MGMT promoter)] were examined for MGMT expression levels. Next, the cells were treated with TTFields (intensity of 0.83 V/cm RMS; frequency of 200 kHz) using the inovitro system. Cell count and colony formation were employed to detect the effectiveness of TTFields concomitant with TMZ and/or CCNU. Western blot allowed the detection of expression levels of DNA repair proteins in control versus TTFields-treated cells. RESULTS The cell lines displayed comparable responses to TTFields and CCNU, while they differed in sensitivity to TMZ according to MGMT expression status. TTFields concomitant with TMZ displayed an additive effect, irrespective of MGMT expression levels. The effect of concomitant TTFields with CCNU was additive in MGMT-expressing cell lines, whereas it trended toward synergy in MGMT-non-expressing cell lines. Expression of proteins from the Fanconi Anemia (FA)-BRCA pathway for DNA repair was downregulated following TTFields application. TTFields concurrent with both TMZ and CCNU provided higher efficacy relative to TMZ plus CCNU or TTFields apart, with additivity in MGMT-expressing cell lines and a tendency toward synergy in MGMT-non-expressing cell lines. CONCLUSION The results support the clinical benefit demonstrated for concomitant TTFields with TMZ plus CCNU, showing that the efficacy of TMZ and CCNU may be enhanced by TTFields, with synergism seen for the latter case in cells not expressing MGMT. The BRCAness state induced by TTFields rationalizes this, as in the absence of MGMT DNA damage induced by CCNU requires the FA-BRCA pathway for repair.
P06.18.B OVERVIEW OF THE GLITIPNI TRIAL - LOCAL ADMINISTRATION OF IMMUNE CHECKPOINT INHIBITION AND/OR DENDRITIC CELLS FOLLOWING RESECTION OF RECURRENT GLIOBLASTOMA
Authors: J Duerinck, J Tijtgat, I Dirven, W Geens, S Brock, A Michotte, X Geeraerts, L Stevens, S Thuyaerts, H Everaert, A Vanbinst, M Bruneau, A Rogiers, B Neyns
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Intravenous (IV) administration of the Immune checkpoint inhibitor (ICI) nivolumab (NIVO) for recurrent glioblastoma (rGB) has proven mostly ineffective, and the combination of IV ipilimumab (IPI) plus nivolumab (NIVO) is associated with a high incidence of irAE. Combinatorial immunotherapy strategies are likely to be more effective, and direct Intracerebral (iCE) administration following the resection of rGB could be a more effective and safer alternative to iv-dosing METHODS We previously demonstrated that intra-operative intracerebral (iCE) administration of the Immune checkpoint inhibitors (ICI) ipilimumab (IPI) and nivolumab (NIVO) after resection of recurrent glioblastoma (rGB) is safe and resulted in encouraging survival. The adaptive phase I Glitipni trial was further expanded with more cohorts (C) exploring the implantation of an Ommaya reservoir for intracavitary (iCav) administration of escalating doses of ICI, complementary iCE injection of increasing numbers of myeloid dendritic cells (myDC). We provide an overarching overview of all patients included in the program. RESULTS 102 patients have been included in the Glitipni trial. In C1 and 2 (3 and 24 patients) iCE IPI and IPI+NIVO were followed by IV NIVO every two weeks. Next, we combined this peroperative backbone with postoperative iCav injection of NIVO 1-/5-/10 mg every two weeks through an Ommaya reservoir following stereotactic biopsy (C3, 16 patients) or resection (C4, 16 patients). No dose-related toxicity was seen for iCav NIVO. iCE injection of BDCA-1 and BDCA-3+ myDC (escalating from 1-/10- to 20.10E6) was added to the backbone of C3/4 with adjuvant 10mg iCav NIVO (resection in C5, 11 patients, biopsy in C6, 2 patients). In C7 (27+patients), patients had resection, iCE IPI+NIVO, and postoperative IV NIVO with iCav NIVO 10mg and IPI escalating 1/5/10mg. Dose limiting toxicity (aseptic neutrophilic pleocytosis) was encountered with iCav IPI (5-10mg Q2w). Median Overall Survival (mOS) was 38 weeks (C1/2), 23 weeks (C3), 42 weeks (C4), 44 weeks (C5/6) and 40 weeks (C7) CONCLUSION Peroperative iCer administration of IPI and NIVO is feasible and associated with an acceptable safety profile. A potential beneficial effect on overall survival was restricted to patients with resectable recurrences. Addition of myDC my improve PFS and OS. There is no indication for an additional benefit of adjuvant iCav IPI or NIVO. Further research will expand on iCer myDC administration and investigate complementary neo-adjuvant ICI administration.
P21.03.A CDKN2A/B VERSUS MORPHOLOGY IN DIAGNOSING WHO GRADE 4 IDH MUTATED ASTROCYTOMAS: WHAT IS THE CLINICAL RELEVANCE?
Authors: A E Lipatnikova, A Denés, T Olsson Bontell, H Carén, S Ferreyra Vega, T Kling, A S Jakola
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND In the 2021 WHO classification system, the glioma subgroup IDH-mutated astrocytomas grade 4 was introduced, and diagnosis can be based upon molecular or histopathological morphological criteria. We here explore if the reason for a diagnosis of WHO grade 4 IDH mutated astrocytoma influences survival. MATERIAL AND METHODS Twenty-five patients with a revised diagnosis of IDH-mutated astrocytoma grade 4 were included. Patients were divided in three groups based upon the; (i) Morphological high grade (necrosis and/or microproliferation in microscopy); (ii) Molecular high grade (homozygous CDKN2A/B homodelation); (iii) Both morphological and molecular high grade. Inclusion period was 2007-2018 for molecular high grade and 2012-2018 for morphological high grade. All patients had potential for at least 5 year follow-up. RESULTS The median survival following surgery was 5.2 years (Q1-Q3 2.9-7.0 years). The median age was 42 years (Q1-Q3 33-59). As expected the tumors had the frontal lobe predominance (72%). Seizures were the most common debut symptom, occurring in 48% of patients. There were 12 patients in group (i), nine patients in group (ii), and four patients in group (iii). Group (iii) with both morphological and molecular WHO grade 4 criteria was characterized by a significantly worse prognosis with a median estimated survival of 2.8 years (p = 0.002). There was no substantial difference in overall survival between groups (i) and (ii) (7.3 years vs 5.2 years, p = 0.237). CONCLUSION The median survival of IDH-mutated astrocytoma grade 4 is approximately five years, while prognosis seems to be significantly worse for the minority of patients where the tumor fulfills both molecular and morphological criteria. More research into larger cohorts is encouraged.
P12.12.A DISTRIBUTION AND TUMOR CELL PROXIMITY OF IMMUNE CELLS IN THE TUMOR CORE, TRANSITION ZONE AND PERIPHERY OF GLIOBLASTOMAS
Authors: V Pedersen, A Møldrup Knudsen, S Regner Michaelsen, B Winther Kristensen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma is the most frequent and malignant brain tumor. Immune therapies have had limited effect but not much is known about the frequency and type of immune cells in the transition zone and periphery of the tumors. In these areas, tumor cells migrate into the brain parenchyma and prevent total tumor resection thereby leading to recurrence. This study aims to quantify the type and distribution of immune cells in glioblastomas. MATERIAL AND METHODS A cohort of 67 glioblastomas with strong P53 immunoreactivity in the tumor cells was established. Slides contained tissue from central tumor and/or transition zone and/or tumor periphery. A chromogenic multiplex was established, where tissue sections were stained with P53 (tumor cells), FOXP3 (FOXP3+ regulatory T cells), CD8 (CD8+ cytotoxic T cells) and IBA1 (microglia/macrophages). Cells were counted in tumor core, transition zone and periphery using Visiopharm software based on training of convolutional neural networks. Moreover, the number of tumor cells with immune cells in proximity (30 µm) was quantified, and the distance from a reference cell to another cell type within 30 µm was calculated. RESULTS The densities of CD8+, FOXP3+ and IBA1+ cells were significantly higher in the core (10, 1 and 473 cells/mm2) than in the periphery (3, 0,2 and 179 cells/mm2) (P &amp;lt; 0.001), and in the transition zone (10, 1 and 396 cells/mm2) than in the periphery (P &amp;lt; 0.001). However, the CD8+ and IBA1+ cells/tumor cell ratio increased from core (0,004 and 0,18) to transition zone (0,01 and 0,36) and to periphery (0,015 and 0,8) (P &amp;lt; 0.001). The highest density of tumor cells with CD8+ cells in proximity was in the tumor core (55 cells/mm2 in core, 22 cells/mm2 in transition zone, 3 cells/mm2 in periphery) (P &amp;lt; 0.001), whereas the highest density of tumor cells with IBA1+ cells (1412 cells/mm2 in core, 7412 cells/mm2 in transition zone, 98 cells/mm2 in periphery) and FOXP3+ cells (0 cells/mm2 in core, 3 cells/mm2 in transition zone, and 0 cells/mm2 in periphery) in proximity was in the transition zone (P &amp;lt; 0.001). CONCLUSION Although levels of immune cells are highest in the tumor core - the higher proximity and ratio of immune cells to tumor cells in the transition zone/periphery suggest immune-suppressive mechanisms to be active in these areas.
P07.09.B A RANDOMIZED PHASE 2B STUDY OF SURVIVIN VACCINE SURVAXM PLUS ADJUVANT TEMOZOLOMIDE FOR NEWLY-DIAGNOSED GLIOBLASTOMA (SURVIVE)
Authors: M S Ahluwalia, M Ciesielski, A Abad, D Reardon, R Aiken, M Barbaro, K Sinicrope, D M Peereboom, Y Odia, A Brenner, V Venur, N Butowski, A Belal, J Qiu, A Ozair, A A Khosla, C Schilero, S Figel, D Casucci, L Mechtler, R Fenstermaker
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Newly-diagnosed glioblastoma (nGBM) has a dismal prognosis with a median overall survival (OS) of nearly 16 months. nGBM cells have high expression of tumor-associated survivin protein. Survivin, localized to the cell surface through presentation by MHC class I molecules, is recognized by antibodies and cytotoxic T-lymphocytes (CTLs). A Phase 2a trial (NCT02455557) showed that a 15-amino acid-peptide-conjugate vaccine (SurVaxM) stimulates the production of survivin-directed antibodies and anti-tumor CTL in nGBM patients, resulting in a median OS of 25.9 months. This Phase 2b randomized controlled trial (RCT) aims to further investigate the efficacy of SurVaxM and adjuvant temozolomide for nGBM. METHODS This multicenter, placebo-controlled, investigator- and patient-blinded, in-progress RCT randomizes nGBM patients receiving standard of care to either SurVaxM (arm A) or saline placebo (arm B) in a 3:2 ratio at 15 sites. Included patients have age ≥18 years, normal organ function, Karnofsky Performance Status (KPS) ≥70, surgical resection, residual MRI contrast enhancement of ≤1 cm3 within 72 hours of resection, and adjuvant temozolomide (TMZ) therapy. Patients with recurrent, multicentric, brainstem- or cerebellar-origin GBM are excluded, as well as patients on tumor-treating fields or other immunotherapies. All patients undergo 3 phases: (1) vaccine priming (VP) phase, starting within 4 weeks after completion of chemoradiation, where 4 doses of SurVaxM or Placebo are administered every 2 weeks; (2) adjuvant TMZ phase, started after ≥1 VP dose; and (3) vaccine maintenance phase, started 8 weeks after VP, with SurVaxM or placebo given every 8 weeks. TMZ phase overlaps with VP and VM phases. The primary endpoint is median OS. Assuming a 1-year survival rate of 75% in the SurVaxM arm, comparable to the median OS in early phase trials, and 60% in the control arm, the study will enroll 265 patients, 159 in arm A and 106 in arm B. A log-rank test stratified by KPS (70-80 and 90-100), MGMT status (methylated and unmethylated), and IDH status (mutant and wild-type) will be used for analysis. Secondary endpoints per study arm are survival at 15, 18, and 24 months, median progression-free survival, toxicity, and progression-free survival at 3, 6, and 12 months. A single sequential OS-driven interim analysis is planned when 50% of OS events (deaths) occur. The study is expected to take 35 months, with ongoing accrual. RESULTS 69 patients have been enrolled as of April 11, 2023. CONCLUSION Findings from this trial will demonstrate the safety and efficacy of survivin vaccine in GBM (Clinical trial information: NCT05163080).
JS06.4.A MULTI-OMIC CHARACTERIZATION OF LUNG CANCER BRAIN METASTASIS REVEALS THE METABOLIC VULNERABILITY AS A NOVEL THERAPEUTIC TARGET
Authors: H Duan, S Wei, Y Liu, G Zhang, Y Mou
Journal: Neuro-Oncology (2023)

Abstract Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A better understanding of the molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs. Here, we performed integrated analyses of both bulk and single cell genomic transcriptomic and proteomic data derived from five published and two newly generated patient cohorts, totaling 141 patients with paired and unpaired primary lung cancer and LC-BrM. This was subsequently validated by immunohistochemistry (IHC) and multiplexed immunofluorescence (mIF) staining. LC-BrMs exhibited significantly lower tumor mutational burden but higher intra-tumor heterogeneity. We observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TP53, MUC16, LRP1B, KRAS, FAT3, and NF1. In addition, the genome-wide landscape of somatic copy number alterations (SCNAs) was found to be similar between primary lung cancers and LC-BrM lesions. Nevertheless, three regions of focal amplification were significantly enriched in LC-BrMs, including 11q13.1, 14q11.2, and 12p13.31. Integrated analyses of transcriptional and proteomic data revealed mitochondrial-specific metabolism was activated in LC-BrMs and accompanied by a suppressed tumor immune microenvironment, which was further corroborated by IHC and mIF data. Importantly, targeting oxidative phosphorylation with gamitrinib in combination with anti-PD1 immune checkpoint blockade (ICB) therapy significantly improved the survival of mice with LC-BrMs. In conclusion, our findings not only provide comprehensive and multi-omic perspectives of the molecular mechanisms of LC-BrMs but also contribute to the development of potential therapeutic strategies with the goal of translating it into clinical trials for patients with LC-BrMs.
P07.01.A MR-GUIDED LITT THERAPY IN PATIENTS WITH PRIMARY IRRESECTABLE GLIOBLASTOMA: A CONTROLLED, PROSPECTIVE PILOT STUDY (EMITT PILOT-STUDY)
Authors: I Viozzi, C Neutel, C G Overduin, A Rijpma, M M Rovers, M ter Laan
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Laser interstitial thermal therapy (LITT) is growing as a minimally invasive procedure in the treatment of brain tumours, even if high-quality evidence is lacking. We aimed to assess practical feasibility of a randomized controlled trial (RCT) in patients with primary irresectable glioblastoma (nGBM) and to collect pilot data on technical feasibility and safety of LITT. METHODS Adult patients with radiologically suspected glioblastoma where the multidisciplinary tumour board advised biopsy-only with KPS ≥70 and feasible trajectories to reach ≥70% ablation were prospectively included. Patients were randomized to receive either biopsy combined with LITT or biopsy alone, followed by chemoradiation (CRT). Main endpoints were practical feasibility of RCT (inclusion rate, willingness to be randomized and ability to complete the follow-up procedures), technical feasibility (time from indication to procedure, time from procedure to CRT, duration of procedure) and safety (complications reported following the Clavien Dindo classification (CD). RESULTS A total of 15 patients with an irresectable nGBM were included in the study (5 in the control and 10 in the LITT arm). Patients were highly motivated to participate to the study and all patients completed the follow-up procedure. After including 9 patients randomization was stopped. All patients were planned within 2 weeks after indication and no delay was observed in referring patients for adjuvant CRT. One, two or three laser probes were used to reach ≥70% expected ablation. Total procedure time varied between 200-540 minutes. Two CD≥3 complications occurred in the LITT arm. CONCLUSION Our pilot data suggest an RCT investigating LITT in patients with an irresectable nGBM is feasible, with initial safety data appearing in line with that of tumour resection. As a next step, we have designed a national multicenter RCT in order to evaluate survival benefit, quality of life and cost-effectiveness of LITT in this population.
P10.14.B PROGRESSION OF IDH-MUTANT ASTROCYTOMAS TO GRADE 4 UNDER TREATMENT-RELATED SELECTION PRESSURE
Authors: K J Rautajoki, S Jaatinen, A Hartewig, A M Tiihonen, M Annala, I Salonen, M Valkonen, V Simola, E M Vuorinen, A Kivinen, M J Rauhala, R Nurminen, K K Maass, S Lahtela, A Jukkola, O Yli-Harja, P Helén, K W Pajtler, P Ruusuvuori, J Haapasalo, W Zhang, H Haapasalo, M Nykter
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, therefore a better understanding of this process is of paramount importance for improved patient care. MATERIAL AND METHODS We analyzed next-generation sequencing data from matched IDH-mutant astrocytomas before and after progression to grade 4 from up to 27 patients as well as publicly available The Cancer Genome Atlas (TCGA) data from up to 595 cases. All patients in our discovery cohort with genome-wide sequencing data received radiation, all but one underwent chemotherapy, and no patient received temozolomide before progression to grade 4. RESULTS One case in the discovery cohort exhibited a hypermutation signature associated with inactivation of the MSH2 and DNMT3A genes. In other patients, the number of novel chromosomal rearrangements and deletions increased in grade 4 tumors. Tumor progression was associated with upregulated cell cycle progression, migration, and DNA damage repair-related genes. Upon progression, the cell cycle checkpoint genes CDKN2A or RB1 were most commonly inactivated, especially after postoperative radiation and chemotherapy, followed by activating growth factor receptor gene alterations in cases with homozygous CDKN2A deletion. We also detected alterations in DNA repair pathway genes associated with therapy resistance and the promotion of error-prone DNA repair, thus facilitating tumor progression. The homologous recombination repair gene RAD51B was hemizygously deleted in all but one progressed tumor in our discovery cohort. In our retrospective nonrandomized survival analysis, treatment including both radio- and chemotherapy improved relapse-free and overall survival compared to other treatments in cases with primary grade 3 diagnosis. Similar benefit was not observed for cases with primary grade 2 diagnosis, and radiation as sole postoperative treatment was not significantly improving the prognosis in any of the analyses. CONCLUSION Our results support the previous notions that treatment-induced DNA damage can contribute to tumor progression to grade 4 and suggest that altered DNA repair has a role in treatment resistance and tumor progression.